Liquid pharmaceutical compositions

ABSTRACT

A liquid pharmaceutical composition of a GABA analog comprising at least one polyhydric alcohol containing 2 to 6 carbon atoms having a pH of about 5.5 to about 7.0 and additionally a two-component liquid pharmaceutical composition comprising a first component comprising a powder mixture comprising a GABA analog and a solid polyhydric alcohol, and a second component comprising a liquid base are described, as well as methods to prepare the compositions and a method for treating cerebral diseases, including epilepsy, faintness attacks, hypokinesia and cranial traumas, neurodegenerative disorders, depression, mania and bipolar disorders, anxiety, panic, inflammation, renal colic, insomnia, gastrointestinal damage, incontinence, pain, including neuropathic pain, muscular pain, skeletal pain, and migraine using a therapeutically effective amount of the pharmaceutical compositions.

FIELD OF THE INVENTION

[0001] This invention relates to liquid pharmaceutical compositionscomprising a gamma-aminobutyric acid (GABA) analog and processes for thepreparation of the same as well as methods of using such compositions totreat subjects, including human subjects, suffering from certaincerebral diseases, including epilepsy, faintness attacks, hypokinesiaand cranial traumas, neurodegenerative disorders, depression, mania andbipolar disorders, anxiety, panic, inflammation, renal colic, insomnia,gastrointestinal damage, incontinence, pain, including neuropathic pain,muscular pain, skeletal pain, and migraine.

BACKGROUND OF THE INVENTION

[0002] GABA is an inhibitory amino acid found in the mammalian centralnervous system (CNS). It has been reported that dysfunctions with GABAneurotransmission in the CNS may contribute or even cause psychiatricand neurological diseases such as epilepsy, schizophrenia, Parkinson'sdisease, Huntington's Chorea and dyskinesia (Saletu B., et al.,International Journal of Clinical Pharmacology, Therapy, and Toxicology,1986; 24:362-373).

[0003] Gabapentin (1-(aminomethyl)-cyclohexaneocetic acid):

[0004] was designed as a GABA analog that would cross the blood-brainbarrier. Gabapentin was found to have anticonvulsant and antispasticactivity with extremely low toxicity in man. Gabapentin is presentlymarketed under the trademark Neurontin® as adjunctive therapy in thetreatment of partial seizures in patients with epilepsy.

[0005] U.S. Pat. Nos. 4,024,175 and 4,087,544 disclose the use ofgabapentin for the treatment of certain forms of epilepsy, faintnessattacks, hypokinesia, and cranial traumas. Additionally, gabapentinbrings about an improvement of cerebral functions and thus is useful intreating geriatric patients. U.S. Pat. No. 5,084,479 discloses the useof gabapentin in neurodegenerative disorders. U.S. Pat. No. 5,025,035discloses the use of gabapentin in treating depression; U.S. Pat. No.5,510,381 discloses the use of gabapentin in treating mania and bipolardisorders. U.S. Pat. No. 5,792,796 discloses the use of gabapentin intreating anxiety and panic. U.S. Pat. No. 6,127,418 discloses the use ofgabapentin in treating gastrointestinal damage; U.S. Pat. Nos. 4,894,476and 4,960,931 disclose a novel crystalline monohydrate form ofgabapentin; and U.S. Pat. Nos. 5,133,451; 5,319,135; 5,362,883;5,693,845; 5,091,567; and 5,068,413 disclose processes for preparinggabapentin as well as intermediates used in these processes. All of theaforementioned U.S. Patents are incorporated herein by reference.

[0006] Pregabalin ((S)-4-amino-3-(2-methylpropyl)butanoic acid)

[0007] is another GABA analog disclosed in U.S. Pat. No. 5,563,175 forthe treatment of seizure disorders including epilepsy, which is hereinincorporated by reference.

[0008] U.S. Pat. No. 6,117,906 discloses the use of pregabalin intreating anxiety; U.S. Pat. No. 6,001,876 discloses the use ofpregabalin in treating pain; U.S. Pat. No. 6,127,418 discloses the useof pregabalin in treating gastrointestinal damage; and U.S. Pat. Nos.5,599,973; 5,608,090; 5,684,189; 5,710,304; 5,616,793; 5,629,447;5,637,767; 5,840,956; 6,046,353; and 6,028,214 disclose processes forpreparing pregabalin as well an intermediate used in these processes.All of the aforementioned U.S. Patents are incorporated herein byreference.

[0009] U.S. Pat. No. 4,024,175 discloses the administration ofgabapentin enterally or parenterally within wide dosage ranges in liquidand solid form. Subsequently, it was disclosed in U.S. Pat. No.6,054,482, which is herein incorporated by reference, that gabapentinwas converted to a lactam, i.e., 2-azaspiro[4.5]decan-3-one:

[0010] Furthermore, lactam formation unexpectedly occurred in the solidphase and under dry storage conditions. Since the gabapentin lactamdisplayed a certain toxicity, levels of this compound must be reduced toa minimum for reasons of safety. In further investigations, it wasconfirmed that liquid formulations of gabapentin undergo cyclization toform lactam much more readily than in the solid state. Additionally, itwas discovered that gabapentin has a very bitter taste. Finally, thereis a need to administer high doses of gabapentin in the treatment ofcertain diseases. In some cases, doses of up to 1500 mg per day aregiven to patients.

[0011] In view of the above issues, pharmaceutical compositions ofgabapentin have been limited to solid dosage forms, such as capsules andtablets.

[0012] Pregabalin, similar to gabapentin, also is prone to cyclizationto a lactam, i.e., 4-isobutyl-pyrrolidin-2-one:

[0013] Thus, there is a need for a liquid pharmaceutical composition ofGABA analogs. In particular, liquid formulations of gabapentin andpregabalin would be desirable for the treatment of small children andelderly patients, since these patient groups require doses of gabapentinor pregabalin which are easy to swallow and which can be individuallydosed.

[0014] The object of the present invention is a liquid pharmaceuticalcomposition which is amenable to high concentrations of a GABA analog,is stable, has low levels of lactam, and has an agreeable taste.

[0015] We have surprisingly and unexpectedly found that a GABA analogcan be formulated in a stable liquid pharmaceutical composition havinglow levels of the GABA analog lactam with a pH of about 5.5 to about 7.0containing at least one polyhydric alcohol. Additionally, the presentcomposition has an agreeable taste.

SUMMARY OF THE INVENTION

[0016] Accordingly, a first aspect of the present invention is a liquidpharmaceutical composition of a GABA analog comprising at least onepolyhydric alcohol containing 2 to 6 carbon atoms having a pH of about5.5 to about 7.0.

[0017] A second aspect of the present invention is a method forpreparing a liquid pharmaceutical composition of a GABA analogcomprising:

[0018] Step (1) adding a polyhydric alcohol containing 2 to 6 carbonatoms to water;

[0019] Step (2) adding a GABA analog to the solution from Step (1); and

[0020] Step (3) optionally adjusting the pH of the composition to about5.5 to about 7.0 to afford the liquid pharmaceutical composition.

[0021] A third aspect of the present invention is a two-component liquidpharmaceutical composition of a GABA analog comprising:

[0022] (a) a first component comprising a powder mixture of a GABAanalog and a solid polyhydric alcohol;

[0023] (b) a second component comprising a liquid base wherein thepowder component from (a) is added to the liquid base from (b) to afforda liquid pharmaceutical composition.

[0024] A fourth aspect of the present invention is a method forpreparing a two-component liquid pharmaceutical composition of a GABAanalog comprising:

[0025] Step (1) mixing a GABA analog with a solid polyhydric alcohol toafford a powder mixture;

[0026] Step (2) mixing a polyhydric alcohol with a sweetener and aflavor in water to afford a liquid base; and

[0027] Step (3) adding the powder mixture to the liquid base to affordthe liquid pharmaceutical composition.

[0028] A fifth aspect of the present invention is a liquidpharmaceutical composition of a GABA analog having less than 0.5% byweight of its corresponding lactam.

[0029] A sixth aspect of the present invention is a method of using aliquid pharmaceutical composition of a GABA analog to treat subjects,including human subjects, suffering from cerebral diseases, includingepilepsy, faintness attacks, hypokinesia and cranial traumas,neurodegenerative disorders, depression, mania and bipolar disorders,anxiety, panic, inflammation, renal colic, insomnia, gastrointestinaldamage, incontinence, pain, including neuropathic pain, muscular pain,skeletal pain, and migraine.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The term “polyhydric alcohol” refers to an alkyl or aliphaticalcohol containing from 2 to 6 carbon atoms and 2 to 6 hydroxyl groups,such as, for example, glycerol, xylitol, sorbitol, mannitol, and thelike.

[0031] The term “GABA analog” refers to a compound derived from or basedupon the structure of gamma-aminobutyric acid, such as, for example,gabapentin, pregabalin, and the like. Other GABA analogs that can beemployed in the liquid pharmaceutical compositions of this invention arethose referred to in Great Britain provisional patent application0125807.8, which was filed on Oct. 26, 2001, Great Britain provisionalpatent application 0109635.3, which was filed on Apr. 19, 2001, and thecorresponding PCT patent application that claims priority from the twoforegoing provisional applications and which was filed in April of 2002.The foregoing applications are incorporated herein by reference in theirentirties. Examples of GABA analogs that are referred to in theforegoing references are set forth below.

[0032] wherein R¹ and R² are each independently selected from H,straight or branched alkyl of 1-6 carbon atoms, cycloalkyl of from 3-6carbon atoms, phenyl and benzyl, subject to the proviso that, except inthe case of a tricyclooctane compound of formula (XVII), R¹ and R² arenot simultaneously hydrogen.

[0033] Suitable compounds (including salts, solvates and pro-drugsthereof) are:

[0034] ((1R,5S)-3-Aminomethyl-1,5-dimethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid;

[0035]

[0036]((1S,5R)-3-Aminomethyl-1,5-dimethyl-bicyclo[3.2.0]hept-3-yl)-aceticacid;

[0037]((1R,5S)-3-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid;

[0038]((1S,5R)-3-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid;

[0039]((1S,2S,5R)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-aceticacid;

[0040] ((1R,2S,5S)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.]hex-2-yl)-acetic acid;

[0041]((1S,2R,5R)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-aceticacid;

[0042]((1R,2R,5S)-2-Aminomethyl-6,6-dimethyl-bicyclo[3.1.0]hex-2-yl)-aceticacid;

[0043] ((1R,5R,6S)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid;

[0044] ((1S,5R,5S,6S)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-aceticacid;

[0045] ((1R,5R,6R)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid;

[0046] ((1S,5S,6R)-6-Aminomethyl-bicyclo[3.2.0]hept-6-yl)-acetic acid;

[0047]cis-((1S,2R,4S,5R)-3-Aminomethyl-2,4-dimethyl-bicyclo[3.2.0]hept-3-yl)-aceticacid;

[0048]trans-((1S,2R,4S,5R)-3-Aminomethyl-2,4-dimethyl-bicyclo[3.2.0]hept-3-yl)-aceticacid;

[0049]((1S,5R,6S,7R)-3-Aminomethyl-6,7-dimethyl-bicyclo[3.2.0]hept-3-yl)-aceticacid;

[0050]((1S,5R,6R,7S)-3-Aminomethyl-6,7-dimethyl-bicyclo[3.2.0]hept-3-yl)-aceticacid;

[0051]((1R,2S,5S)-7-Aminomethyl-3,3-dimethyl-bicyclo[3.3.0.0]oct-7-yl)-aceticacid;

[0052] ((1R,6R,7S)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid;

[0053] ((1S,6S,7S)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid;

[0054] ((1R,6R,7R)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid;

[0055] ((1R,6S,7R)-7-Aminomethyl-bicyclo[4.2.0]oct-7-yl)-acetic acid;

[0056] ((1R,7R,8S)-8-Aminomethyl-bicyclo[5 .2.0]non-8-yl)-acetic acid;

[0057] ((1S,7S,8S)-8-Aminomethyl-bicyclo[5.2.0]non-8-yl)-acetic acid;

[0058] ((1R,7R,8R)-8-Aminomethyl-bicyclo[5 .2.0]non-8-yl)-acetic acid;

[0059] ((1R,7S,8R)-8-Aminomethyl-bicyclo[5.2.0]non-8-yl)-acetic acid.

[0060] [((1R,5R,6S)-6-(Aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid;

[0061] [(1S,5S,6R)-6-(Aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid;

[0062] (1RS,5RS,6RS)-6-(Aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid;and

[0063] [(1RS,6RS,7SR)-7-(Aminomethyl)bicyclo[4.2.0]oct-7-yl]acetic acid.

[0064] The liquid pharmaceutical compositions of the present inventioncomprise a GABA analog, such as, for example, gabapentin, pregabalin,and the like.

[0065] Gabapentin may readily be prepared as described in U.S. Pat. Nos.5,132,451; 5,319,135; 5,362,883; 5,693,845; 5,091,567; and 5,068,413.

[0066] Pregabalin may readily be prepared as described in U.S. Pat. Nos.5,563,175; 5,599,973; 5,608,090; 5,684,189; 5,710,304; 5,616,793;5,629,447; 5,637,767; 5,840,956; 6,046,353; and 6,028,214.

[0067] In preparing liquid pharmaceutical compositions of the compoundsof the present invention, pharmaceutically acceptable carriers aresolids and liquids.

[0068] Liquid form preparations include solutions, suspensions andemulsions, for example, water or certain glycol solutions. Forparenteral injections, liquid preparations can be formulated in solutionin aqueous polyethylene glycol solutions.

[0069] Aqueous solutions suitable for oral use can be prepared bydissolving the active component in water and adding suitable colorants,flavors, and stabilizing and thickening agents as desired.

[0070] Aqueous suspensions suitable for oral use can be made bydispersing the finely divided active component in water with viscousmaterial, such as, natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

[0071] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

[0072] In the liquid pharmaceutical compositions of the presentinvention, it was found that if the formulation is buffered to a pH ofabout 5.5 to about 7.0 undesired lactam formation can be substantiallyavoided. However, this limits the use of certain adjuvants or carriersthat can be used, such as, for example, taste-correcting acids orpreservatives. Preservatives especially suited for oral compositionsusually display their optimum antimicrobial activity in the acid range.Furthermore, the solubility of the usual preservatives, such as aparaben, sorbic acid, or benzoic acid decreases at low storagetemperatures required for the liquid compositions of the presentinvention. Thus, precipitations and/or insufficient antimicrobialactivity due to low concentration of the preservative at these lowtemperatures is to be expected. Salts of the usual preservatives havebetter solubility, but as a rule their antimicrobial activity is tooweak.

[0073] In the development of the liquid pharmaceutical compositions ofthe present invention, it was shown that theoretically most alcoholspossess a preserving and stabilizing action in aqueous solution.However, certain alcohols had undesirable properties and were not usefulin the present pharmaceutical compositions. For example, ethyl alcoholis not desirable for pediatric formulations, propylene glycol and benzylalcohol have an unpleasant taste, and chlorobutanol is not sufficientlystable at a pH of about 5.5 to about 7.0.

[0074] Surprisingly and unexpectedly, it was found that polyhydricalcohols containing 2 to 6 carbon atoms, preferably 3 to 6 carbon atoms,such as, for example, glycerol, xylitol, sorbitol, mannitol, and thelike can be used as adjuvants for oral liquid gabapentin and pregabalincompositions. Preferably, glycerol and/or xylitol are used in the liquidcompositions of the first aspect of the present invention. Theseadjuvants can be used in high concentration in the desired pH range ofabout 5.5 to about 7.0. Preferably, between a pH of about 6.0 to about7.0. They not only act as preservatives and have a stabilizing effect onthe active components, but they also substantially mask the bitter tasteof the active components as a result of their sweet taste andadditionally are noncariogenic. Thus, the use of one or more polyhydricalcohols allows the preparation of acceptably tasting syrups of a GABAanalog especially gabapentin or pregabalin which, when cooled torefrigeration temperatures of about 2° to about 10° C., have a storagestability of at least 2 years. The polyhydric alcohols may be used in aconcentration range of about 25% to about 75% (weight/volume, w/v),preferably about 30% to 75% (w/v) and most preferably about 40% to about75% (w/v). In general, it is not necessary to add additionalpreservatives to the liquid compositions of the present invention.However, the addition of another preservative may be advantageous (forexample, in the case of sterile-filled syrups when the container is usedfor multiple doses to prevent contamination of the container). In thecase of a sterile-filled syrup, care must be taken in choosing anadditional preservative that can be used in the desired pH range (about5.5 to about 7.0) that does not interact with the active components anddoes not accelerate lactam formation. We have found that benzethoniumchloride can be used as an additional preservative.

[0075] Additionally, flavor improvers can be added to the liquidcompositions of the present invention to enhance the taste maskingaction of the polyhydric alcohols. However, only adjuvants which do notcontain a reactive aldehyde or keto functionality can be used, sincethese functionalities react with the active components. Furthermore, theflavor improvers must not alter the desired pH range of about 5.5 toabout 7.0. For example, fruity compositions have proved to be especiallyeffective, such as, for example, aniseed, strawberry and peppermint oraniseed, huckleberry, and peppermint, and the like.

[0076] A storage temperature of about 2° C. to about 10° C., preferablyabout 2° C. to about 8° C. and more preferably about 4° C. to about 7°C. is required to ensure the stability of the active components and thetaste of the liquid composition.

[0077] Furthermore, a liquid pharmaceutical composition of a GABA analogcontains less than 0.5% (weight/weight, w/w) of the GABA analog lactam,preferably 0.4% (w/w) of lactam after storage at about 2° C. to about10° C., preferably about 2° C. to about 8° C. for 18 months to 2 years,preferably 18 months.

[0078] The syrup-like pharmaceutical compositions of the presentinvention can be filled into single or multiple dose containers. Forexample, single dose containers can be a double sachet of coatedaluminum foil which contains two half doses. An example of multiple-dosecontainers are glass or plastic bottles, preferably with childproofclosures. The multiple dose container is variable in dosage volume andcan be provided with an appropriate dosage aid, such as, a measurementbeaker, measurement pipette, and the like.

[0079] Another aspect of the present invention is a two-component liquidpharmaceutical composition of a GABA analog such as, for example,gabapentin, pregabalin and the like. The composition comprises a firstcomponent comprising a powder mixture of a GABA analog and a solidpolyhydric alcohol, such as, for example, sorbitol, xylitol, mannitol,and the like, preferably sorbitol, and a second component comprising aliquid syrup base containing a polyhydric alcohol, such as, for example,glycerol and the like, and one or more flavoring agents, such as, forexample, artificial menthol flavor, artificial aniseed flavor,artificial blueberry flavor, and sugar and water. The liquidpharmaceutical composition is prepared by dissolving the powder blendinto the syrup vehicle at the time the product is dispensed to thepatient. The liquid composition once prepared should be stored at about2° C. to about 10° C., preferably about 2° C. to about 8° C., and morepreferably about 4° C. to about 7° C. However, the liquid compositionmay be stored at room temperature for about 2 months without exceedingundesired levels of lactam as previously described.

[0080] Dosages of gabapentin and pregabalin are well-known in the art,and the skilled practitioner will readily be able to determine thedosage amount required for a subject based upon weight and medicalhistory.

[0081] In general, dosages of gabapentin and pregabalin are disclosed inthe aforementioned U.S. Patents. In particular, dosages of gabapentinare disclosed in U.S. Pat. Nos. 4,024,175; 4,087,544; and 6,054,482 andpregabalin in U.S. Pat. No. 5,563,175.

[0082] The following nonlimiting examples illustrate the inventors'preferred methods for preparing and using the liquid pharmaceuticalcompositions of the present invention.

General Process for Preparing a Liquid Composition of Gabapentin

[0083] Water and glycerol are heated to 40° C. to 50° C., and xylitol isadded with stirring. An endothermic reaction results from thedissolution of the xylitol, and the solution is cooled. After thexylitol is dissolved, the solution is cooled to 30° C. to 40° C., andgabapentin is added with stirring. After the gabapentin is completelydissolved, the flavor is added with stirring at 25° C. to 30° C. Thehomogeneous solution is adjusted to a pH of 5.5 to 7.0, with an acid,such as, 0.1N hydrochloric acid (HCl), or base such as 0.1N sodiumhydroxide (NaOH), and filtered.

[0084] Using the above general procedure, liquid compositions ofpregabalin may be prepared.

[0085] Table 1 contains representative liquid compositions ofgabapentin. TABLE 1 Liquid Composition of Gabapentin Example 1^(a)Example 2 Example 3 Example 4 Gabapentin 2.000 5.000 5.000 5.000 Xylitol20.000 30.000 30.000 29.940 Strawberry/anise 1.000 — — 1.000 flavorHuckleberry/anise — 1.000 1.000 — flavor Glycerol 95% 50.000 40.00030.000 43.790 Hydrochloric acid, — 7.720 — — 0.1 N Sodium hydroxide, — —0.770 — 0.1 N Purified water 27.000 16.280 33.230 20.27 pH value 6.2 5.57.0 6.5

General Process for Preparing a Two-Component Liquid Composition ofGabapentin

[0086] Step [A] Powder Blend

[0087] Gabapentin or gabapentin monohydrate (U.S. Pat. No. 4,894,476) isblended with sorbitol.

[0088] Step [B] Syrup Base

[0089] A sorbitol solution, glycerol, granular sugar, menthol flavor,artificial aniseed flavor, and artificial blueberry flavor are dissolvedin distilled water.

[0090] Step [C] Final Syrup

[0091] The syrup is prepared by dissolving the powder blend from Step[A] into the syrup base from Step [B]. The powder blend is stored inaluminum pouches and the syrup base is stored in a glass bottle at roomtemperature. After preparing the syrup extemporaneously, the syrup isstored under refrigeration.

[0092] Using the above general procedure, two-component liquidcompositions of pregabalin may be prepared.

[0093] Table 2 contains a representative liquid composition ofgabapentin. TABLE 2 Two-Component Liquid Composition of GabapentinPowder Blend Gabapentin Monohydrate 9.90 g (Equivalent to 9.00 ggabapentin) Sorbitol 22.50 g Syrup Base Sorbitol Solution 225.00 gGlycerin, USP 180.00 g Sugar, Granular 45.00 g Artificial MentholFlavor^(a) 56.25 mg Artificial Aniseed Flavor^(b) 22.50 mg ArtificialBlueberry Flavor 4.275 g Water, Distilled qs^(c) to 450 mL

What is claimed is:
 1. A liquid pharmaceutical composition of a GABA analog comprising at least one polyhydric alcohol containing 2 to 6 carbon atoms and wherein said composition has a pH of about 5.5 to about 7.0.
 2. The composition according to claim 1, wherein the polyhydric alcohol contains 3 to 5 carbon atoms and wherein the content of polyhydric alcohol is about 25% to about 75% weight/volume (w/v).
 3. The composition according to claim 2, wherein the polyhydric alcohol is selected from the group consisting of glycerol, xylitol, sorbitol, mannitol, and a mixture of glycerol and xylitol, and wherein the content of polyhydric alcohol is about 40% to about 75% weight/volume (w/v).
 4. The composition according to claim 1, wherein the pH is about 6.0 to about 7.0.
 5. The composition according to claim 1, comprising one or both of: (a) an additional preservative; and (b) an additional flavor improver which does not contain an aldehyde or keto functionality.
 6. A method for preparing a liquid pharmaceutical composition of a GABA analog comprising: Step (1) adding a polyhydric alcohol containing 2 to 6 carbon atoms to water; Step (2) adding a GABA analog to the solution from Step (1); and Step (3) optionally, adjusting the ph of the composition to about 5.5 to about 7.0 to afford the liquid pharmaceutical composition.
 7. The method according to claim 6, wherein the polyhydric alcohol is a mixture of glycerol and xylitol.
 8. The method according to claim 6, wherein the content of polyhydric alcohol is about 25% to 75% (w/v) and the pH is about 6 to about
 7. 9. A two-component liquid pharmaceutical composition of a GABA analog comprising (a) a first component comprising a powder mixture of a GABA analog and a solid polyhydric alcohol; (b) a second component comprising a liquid base wherein the powder component from (a) is added to the liquid base from (b) to afford a liquid pharmaceutical composition.
 10. A method for preparing a two-component liquid pharmaceutical composition of a GABA analog comprising: Step (1) mixing a GABA analog with a solid polyhydric alcohol to afford a powder mixture; Step (2) mixing a polyhydric alcohol with a sweetener and a flavor in water to afford a liquid base; and Step (3) adding the powder mixture to the liquid base to afford the liquid pharmaceutical composition.
 11. The method according to claim 10, wherein the GABA analog is gabapentin or pregabalin.
 12. The composition according to claim 1 or claim 9 wherein the GABA analog is gabapentin or pregabalin.
 13. The composition according to claim 1 or claim 9 wherein said composition has less than 0.5% by weight of the corresponding lactam of the GABA analog.
 14. An aqueous oral pharmaceutical composition of gabapentin or pregabalin, characterized by a content of at least 25% (w/v) of at least one polyhydric aliphatic alcohol containing 2 to 6 carbon atoms and a pH of about 5.5 to about 7.0 containing, less than 0.5% (w/w) of gabapentin lactam or pregabalin lactam, respectively, after storage at 2° C. to 10° C. for 18 months to 2 years.
 15. The pharmaceutical composition according to claim 1 or claim 13 for the treatment of a subject suffering from cerebral diseases, including epilepsy, faintness attacks, hypokinesia and cranial traumas, neurodegenerative disorders, depression, mania and bipolar disorders, anxiety, panic, inflammation, renal colic, insomnia, gastrointestinal damage, incontinence, pain, including neuropathic pain, muscular pain, skeletal pain, and migraine. 